MS is a B cell Disease and Memory B cells are the Target for therapy

Although multiple sclerosis (MS) is considered to be a CD4,Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore it was of interest to find that current MS-treatments, believed to act via T cell inhibition including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+,CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

ProfG was set to go to Lisbon to present at an antibody engineering meeting to talk on "How do antibodies work in MS". Rather than try present his 65 slides in 30min, we aimed to see if we could answer the question. So do alemtuzumab, rituximab/ocrelizumab, daclizumab and natalizumab have anything in common?

Although alemtuzumab depletes T cells, it was evident that memory B cell depletion is marked and it set us thinking as an alternative to the T cell hypothesis.

Surprise surprise, we found papers where some people had similar thoughts (there is no such things as an original idea) but in most cases this was a throw-away idea and was dumped in the midst of many other concepts. However, we had more meat on the story by that time, we saw others work.

One of the odd one being (F below) natalizumab that augmented numbers in the blood, but as the idea is that it stops trafficking into the brain, this should be expected.

Daclizumab is another one of the odd treatments. However once you realise that memory B cells express CD25 and you can see that dacliziumab depletes CD19 B cells, you get in a groove and start looking for it, and find supportive evidence pop-up all over the place. There is also a poster on teriflunomide which supports this concept too.Some publishers wanted too much money for us to include every example for every treatment in the publication. But we give some references if you want to look and the paper is "open source".So this was revelation part one. The next one has additional implications.

Importantly the B memory cell idea gives more insight on ocrelizumab to suggest that CD20 treatment may be over-used to achieve benefit.The data can be interpreted to suggest that ocrelizumab and alemtuzumab could work in the same way (bad news for both companies, sorry). They are probably "both"induction therapies of PIRT (pulsed immune reconsitution therapies)One wonders why such important data has not been properly published? It was dumped in an ECTRIMS abstract in 2012 and an AAN abstract in 2013 (where we found them. Do neurologists have enough time in a couple of hours to see and digest a 1000 posters?) and so there is no excuse from the companies or authors that they have not had enough time to publish the work. There are enough journals desperate for papers.

Now look at the figure above and you will see there is a clear inference that memory B cell levels may be a biomarker for treatment responsiveness.

Looking at figure E it shows only a few people on beta interferon have less than 20% of memory CD19 B cells. Are these the responders? Fingolimod (E) has more, but some failures. In (B) there is more depletion with mitoxantrone and (C) rituximab shows a lot of depletion, which is consistent with its high efficacy in MS.

There are studies in other conditions that use rituximab showing that CD19, CD27 numbers rise in the 4 months before a relapse and can be used as a biomarker to inform on retreatment such that one may be able to use 2/3 less rituximab, which is both safer and cheaper and takes us some way forward to personalised medicine.In some treatments there are some indivudals that make more memory B cells and treatments that do this have in some cases been associated with MS worsening

Importantly memory B cells are the population of cells that accumulates in the CNS in MS and they express the EBV receptor, so depletion of the memory B cell subset depletes the antigen presenting cell that can activate T cells, or perhaps it eliminates the viral reservoir and removes the trigger of MS. In many cases both unswitched (Have not change the antibody subtype they can produce) and switched (IgM and IgD are down regulated and IgG is upregulated from the unswtichted to switched) memory B cells are affected. Which subset is the critical one, the one that has already been reported to be increased in MS.

The T cell immunologists, will have a hard time with this concept, and their stock answer it is because it blocks antigen presentation, but the simple answer is what data argues against this concept? Is the data that suggests a T cell action solid or is it simply circumstantial. Have a read of the paper for your self it is open access (CLICK to DOWNLOAD).

We suggests ways forward to perhaps make treatments safer and better.

Maybe the data miners out there can do some trawling and see what's against the idea. Send them (paper titles) in and lets see if the idea flies.

We have thrown down the gauntlet, and if read, people will either agree or disagree.

38 comments:

I believe in the B cell hypothesis you are offering here, but I think that there is something else at play that is still elusive. If you are selective in what you look for in terms of treatment impact, I wonder if you would find other changes in the body occurring with medical intervention for MS? Perhaps you would show that there are other depletions... and that would send you down a totally different rabbit hole.

Clearly B cells are an issue. But are they the whole issue?

And if you do identify rogue B cells as the culprit - then what does that mean, not just for prevention, but for the root cause of the disease? What are the correlations between B cells and Vitamin D? B cells and EBV?

Once upon a time T cells were seen, again and again, as the target cell. Research went out to support that dogma, and did so again and again. Beware the mistakes of the past.

So must get next paper written to question that EAE experiments are the way to go. Another lead balloon coming your way....Yes we should save the science lemmings and save a load of beasties in the process.

Please read the final paragraph of the paper. The relationship between B cell memory and EBV is there. These cells are the B cells infected by EBV. I suspect vitamin D is important in repertoire and immune development. There is a clear link with diabetes and vitamin D and remember that diabetes starts in childhood so the inference is that the impact will be early in life hence the month of birth effects.

It seems to be a week for rabbit holes and so you are right about putting all eggs in one basket.Quite dangerous but for a long long time most of those eggs have been T cell eggs.

There is a problem that this phenotyping is done using flow cytometry and this outputs in proportions so as one goes down something else goes up. Is it B reg?

But there are some testable questions we are waiting for pharma to trawl their trial data

hahaha... while (i thought) your efforts to link b cells to ebv were a tiny bit less convincing (in the context of causation) then your table setting out the control/destruction of memory b cells by current dmts thought to control ms on basis of t cell action, i was so very impressed by your dedication to tie it all together with a convincing theory :)

you made such a compelling argument: and i agree - disagree with it by using evidence against the info in table 4: if you can do that, we will be all ears to hear the arguments because they could be informative.

I'm not going to give personal or anecdotal reports, but months before my first relapse in my life I had a relapse of a mononucleosis that I thought would kill me.If EBV is linked even to cancers, why would not it be associated with other diseases? Until the scientific community and society itself, it's thought that the outbreak of Zika Virus was directly linked to the numerous cases of Microcephaly in infants in Brazil, there was a last flurry of disbelief and denial.

If EBV is linked even to cancers, why would not it be associated with other diseases?

I suspect (but could be wrong) that there could be a number of diseases thought to be linked to EBV (but not listed in the 'official' list of EBV disease associations). EBV Zika et al..... why on earth would our world pollies care about them while there is no direct association? zika turned out to be visible and so some money was spent on it (on research and on other measures)... but if you can't see it, why care about it? most ebv related diseases don't come with pictures of babies with abnormally shaped heads...

You may even be right that many of the EBV/related diseases "don't cause deformations", but what if EBV really is the driving force behind the development of MS in genetically susceptible individuals? If you have MS you may not have an "apparent" strain on your head because of a virus, but you are having your CNS eaten "inside." So your statement is somewhat incoherent.

Every hypothesis has its "Achilles heel." For example the gender gap the development of MS. Women further develop the disease, it's not an inherited disease but has common genetic factors involved. But someone asks, "How do you explain the cases of MS in men? Is it really related because GA plus oestradiol did not stop the disease?" And a lot of whys who could put hypotheses to the ground. But the important question is: why Ocrelizumab can act on Primary Progressive MS, and the other DMTs have not been able to do this? It is already clear that there is something with B lymphocytes. So checking if EBV can be behind this is perfectly plausible, since it infects B cells. If it were so nobody would but try to find out the cause and involved factors of anything, illness some.

I know what you mean about ideas for free MD. I was doing my postgrad and my supervisor said they hadn't heard before of one idea I suggested. Fast forward a year and I look on their university website page and it said that they are currently working with that idea!I know try and keep my research ideas quiet which is hard to do when I'm enthusiastic.

This looks to me like a good explanation for the natalizumab withdrawal rebound effect. Natalizumab increases b-cells in the blood but blocks them from entering the CNS. When one goes off natalizumab the increased number of b-cells in the blood are now free to enter CNS and lead to the dreaded rebound effect.

How long do you think it will be before Pharma accepts this and focus primarily on B-cells? What does this means for drugs in the pipeline such as ublituximab? Or do you think we need to start from scratch again in developing an effective, targeted treatment?

How does your B cell hypothesis Relate to this :B cellsFor a long time, B cells were thought to be important in MS in their capacityto differentiate into plasma cells and produce antibodies.36 The advent of Bcell depleting therapies has challenged this view. It was noted that clinicalimprovement in patients treated with rituximab often preceded reduction inautoantibody levels.52 Further, in a phase II trial of atacicept, a fusion proteinthat blocks plasma cell function and the late stages of B cell development,treatment was found to aggravate MS.53 This is in contrast to rituximab,which in clinical trials has been proven to be effective in MS.54, 55 The abovesuggests that B cells are important in some other capacity than antibodyproduction. Rituximab treatment results in a noticeable decline of T cellnumbers in CNS of treated patients, suggesting that B cells sustainpathogenic T cell responses. Recently, it was demonstrated that IL-6production is the major mechanism of B cell contribution to the pathogenesisof EAE (experimental autoimmune encephalomyelitis, an experimentalmodel of MS), and also that this inflammatory pathway was increased inRRMS patients.52 Another possibility is that the B cells act as antigenpresenting cells.56Joachim Burman

Where are the anti-CD79a antibodies? There's robust evidence that plasma cells play a role in MS pathogenesis. Intrathecal rituximab + a cd79a antibody could be a true game changer, maybe even a perfect therapy.

Intrathecal is probably not the answer as it is at the bottom of the outflow mechanism..this was shown by the lack of B cell depletion following intrathecal administration..it served to wiper out B cells in the blood. However, your point about targeting the plasma cells is well taken

Thanks for replying"There was aconcomitant depletion of total CSF lymphocytesand B lymphocytes, albeit with low baseline counts.Although the rationale for administering rituximabIT was to achieve an effective therapeutic antibodyconcentration within the BBB, we observed a rapidand potent effect on lymphocytes in the peripheralcompartment"

Only 2 patients had a high enough baselineCSF total cell count to be able to reliably discern achange posttreatment. Both showed an initial depletionof B lymphocytes with a return to baseline by 6months. Total CSF lymphocyte counts also decreasedto almost zero in these 2 patients, which cannot beexplained by B-lymphocyte depletion alone. This is inagreement with previous data on CSF T cells afterrituximab treatment, but the exact mechanisms areunknown.12 The recently described effect of rituximabon a subset of T cells expressing CD20 is aninteresting mechanism that needs to be investigatedfurther.13

A weakness in our study is that we cannot determinewhether changes occurring among lymphocytesubsets in the CSF are an effect of rituximab withinthe CNS compartment or are a result of a peripheraldepletion and subsequently less recruitment into theCSF from PB. It is presently not known whetherappropriate effector mechanisms exist in the CSF tomediate lysis by injected monoclonal antibodies.However, there is now believed to be an inflammatorymilieu along the meninges in many cases ofPMS14 that could possibly facilitate bothcomplement-mediated lysis and antibody-dependentcytotoxicity. There are also data indicating increasedcomplement activation in MS, with the highestoccurrence among progressive patients.15 Furthermore,it was shown that IT administration of anti-CD20 monoclonal antibody could reduce theamount of B lymphocytes in the meninges in EAEwith a concomitant modest amelioration of the clinicalcourse.https://www.ncbi.nlm.nih.gov/pubmed/25745637

The Peripheral Blood B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period. Depletion occurred

By contrast, the initially completely suppressed B and plasma cells in both the blood and CSF reappeared after 5 and 10 months, CSF cells.

There was reduction of T cells after rituximab, but if you look at the data this was months after the treatment. So rather than antibody killing T cells to control disease, one could argue the control of disease lead to drop in cells being retained in the CNS.

Do you think The CD20 expression by T cells is the answer or is it the cop-out that allows t cell immunolologists to keep going :-(

Interesting MD. Very interesting. It seems the intrathecal route is not the answer. What would happen if the antibodies were delivered into the CSF of the cranium? I think at that point HSCT using small molecules becomes a lot safer and easier but it's interesting to think about at least.

ThanksFor your contribution .Only have acess to the second paperThe others papers that csf b cells depletion is modest and OCB continueDo you think that OCB positive are a good marker for poor disease outcome?

Kills every immune cell, hair cell, sperm cell, intestine cell..OK I'm being dramatic however, it only kills proliferating cells and so may miss stuuf and unless HSCT uses cyclophosphamide it doesn't target the CNS

A handful of cases of MS patients treated with allo-HCT for malignant hematological disease have been published [1]. In two recent reports continued disease activity was observed after transplantation [9, 10]. In our patient allo-HCT was associated with the disappearance of IgG oligoclonal bands. This has also been observed in auto-HCT-treated MS patients [2]. However, serial CSF studies showed that even though IgG oligoclonal bands disappeared, CXCL13 and MMP-9 concentrations were increased. CXCL13 is expressed in perivascular infiltrates and within the brain parenchyma in MS, and CSF concentrations of CXCL13 are increased in secondary progressive MS [5, 11]. Secondary progressive MS patients with a more severe disease course harbor lymphoid follicle-like structures in the meninges, and CXCL13 may be involved in the generation of these structures [12]. MMP-9 in CSF has also been associated with disease activity in MS [13]. In an autopsy study it was observed that although lymphocytes and plasma cells were almost absent after auto-HCT, there was ongoing microglia activation, demyelination, and axonal pathology [14]. We hypothesize that CXCL13 and MMP-9 detected in the CSF of our patient may reflect ongoing, pathogenic, immune activation associated with continuing tissue damage even after the eradication of intrathecal IgG synthesis. This is consistent with the notion that progressive MS may depend more on innate than on adaptive immune activationhttps://www.ncbi.nlm.nih.gov/pubmed/22740825

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